FDA Defends Decision on Avastin

By ALICIA MUNDY

WASHINGTON—The government's top cancer-drug regulator defended the recent decision to revoke approval of the drug Avastin for breast cancer, saying the manufacturer, Genentech, was repeatedly warned that some key data were inadequate.

The Food and Drug Administration has been under attack from Republicans in Congress and swamped by petitions from patient groups since the mid-December move. They say the FDA made its decision based on Avastin's cost, roughly $88,000 a patient a year, and they accuse the agency of ignoring evidence of patient benefit.

Richard Pazdur, the longtime director of the FDA's cancer division, said Genentech's assertions of benefit don't hold up. In an interview, he said the agency did not discuss cost. The FDA has approved more expensive drugs, said agency officials. Doctors can still prescribe Avastin, since it retains its approval for four other cancers including colon and lung cancer, said Dr. Pazdur. Some insurers have said they won't cover it for new patients.

"We made the decision because the drug has a marginal effect on tumor growth in breast cancer and in light of Avastin's severe side effects, the risks outweigh the limited benefit," he said. Avastin doesn't help patients' overall survival, he said, which Genentech, a unit of Roche Holding AG, confirms.

Dr. Pazdur zeroed in on a key study, called E2100, that Genentech says showed Avastian can delay tumor growth in patients with advanced breast cancer for five months.

"There were always issues with this trial [and] problems," he said. The FDA warned Genentech years ago that the trial lacked the standards needed to demonstrate Avastin's efficacy in breast cancer, he said.

Genentech is appealing the FDA's decision and has asked for a formal hearing. It defended the E2100 trial. The FDA will grant a hearing if Genentech has new evidence, the agency said.

"We do believe and continue to believe that the E2100 study results are robust," said Sandra Horning, the head of Genentech's global clinical oncology development program, in an interview.

The E2100 trial began in 2001. "It wasn't originally proposed as a drug approval study" for breast cancer, said Dr. Pazdur, which Genentech confirmed. He said if E2100 had originally aspired to that, it would have needed tighter controls to ensure standard data collection and objective readings of scans assessing tumor growth.

FDA records and reports used at public meetings in 2007 and 2010 say E2100 is missing about 10% of the X-ray follow-up scans. An independent review of patient-scan data came to different conclusions from study investigators numerous times, Dr. Pazdur said, calling it a "serious discordance" that cast doubt on the trial results.

In early 2008 the FDA gave conditional approval to Avastin for breast cancer anyway, provided Genentech completed additional supporting studies. Two later trials, said Dr. Pazdur, showed minimal if any delay of tumor growth and "nowhere near five months." That's why the FDA revoked approval, he said, adding that the drug has "life-threatening" side effects such as hemorrhaging and stomach perforations.

Genentech's Dr. Horning said that the FDA had "some issues" related to the way the company wanted to analyze the E2100 trial, but "those were then addressed to their satisfaction." She said it's common for doctors to disagree over scan interpretation and the discrepancies were no worse than those for two other breast-cancer drugs that the FDA approved.

There have been hundreds of reports from individual patients and doctors that Avastin treatment saved them when other medicines had no effect. Dr. Pazdur said those anecdotes are moving but aren't evidence.

"People need to understand that breast cancer patients have only been taking Avastin in combination with Taxol," one of the most powerful chemotherapies and most successful medicines in treating breast cancer, he said.

Joseph Sparano, a cancer doctor at Montefiore-Einstein Center for Cancer Care in New York, said the FDA made the wrong call. Dr. Sparano, whose group has done research on Avastin for Genentech, said he believes that the drug, taken with Taxol, has helped delay tumors spreading to other organs in some of his patients. "Those patients desperately need as many options as possible," he said.

Cancer groups have split over the FDA's decision. While some are backing Genentech, one influential advocacy group in Washington that often calls for greater access to drugs, Friends of Cancer Research, is supporting Dr. Pazdur this time.

"When Avastin received accelerated approval people were very excited about a new option for breast cancer patients. Unfortunately, the confirmatory data didn't fully support the original studies," said Ellen Sigal, the group's chairwoman.

Dr. Pazdur said, "We really wanted the trials to be positive for patients" because "all of us have been touched by this disease." There may be a subset of women with breast cancer who could be helped by Avastin, but Genentech needs to figure out who they are, he said.

via online.wsj.com

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